5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft.

Abstract

Somatic mutations in Isocitrate Dehydrogenase 1 (IDH1) are frequent in low grade and progressive gliomas and are characterized by the production of 2-hydroxyglutarate (2-HG) from α-ketoglutarate by the mutant enzyme. 2-HG is an "oncometabolite" that competitively inhibits α-KG dependent dioxygenases resulting in various widespread cellular changes including abnormal hypermethylation of genomic DNA and suppression of cellular differentiation. Despite the growing understanding of IDH mutant gliomas, the development of effective therapies has proved challenging in part due to the scarcity of endogenous mutant in vivo models. Here we report the generation of an endogenous IDH1 anaplastic astrocytoma model which rapidly grows in vivo, produces 2-HG and exhibits DNA hypermethylation. Using this model, we have demonstrated the preclinical efficacy and mechanism of action of the FDA approved demethylating drug 5-azacytidine in vivo. Long term administration of 5-azacytidine resulted in reduction of DNA methylation of promoter loci, induction of glial differentiation, reduction of cell proliferation and a significant reduction in tumor growth. Tumor regression was observed at 14 weeks and subsequently showed no signs of re-growth at 7 weeks despite discontinuation of therapy. These results have implications for clinical trials of demethylating agents for patients with IDH mutated gliomas.

• Authors: Alexandra Borodovsky, Vafi Salmasi, Sevin Turcan, Armida W M Fabius, Gilson S Baia, Charles G Eberhart, Jon D Weingart, Gary L Gallia, Stephen B Baylin, Timothy A Chan, Gregory J Riggins
• Journal: Oncotarget (Oncotarget) Vol. 4 Issue 10 Pg. 1737-47 (Oct 2013) ISSN: 1949-2553 [Electronic] United States
• PMID: 24077805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Azacitidine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Azacitidine (pharmacology)
• Brain Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Differentiation (drug effects)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• DNA Methylation (drug effects)
• Female
• Glioma (drug therapy, enzymology, genetics, pathology)
• Humans
• Immunohistochemistry
• Isocitrate Dehydrogenase (genetics, metabolism)
• Male
• Mice
• Mice, Nude
• Mutation
• Xenograft Model Antitumor Assays